Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Wu, Jing; Cheng, Panpan; Huang, Zhenguang; Tan, Qingyuan; Qu, Yang

doi:10.1002/biof.1505

Cited by 3 publications

(3 citation statements)

References 38 publications

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“…These data are consistent with our previous observation that reduction in invasion, upon pharmacological and genetic inhibition of the ACVR1C receptor, correlated with decrease in ZEB1 and Snail protein levels, in multiple retinoblastoma lines [3]. Other studies have shown that Nodal controls migration and invasion in several tumor types by modulating the expression of Snail, Slug and ZEB1 [8, 10, 12, 36]. We therefore postulate that ZEB1 and Snail might mediate, at least in part, the effects of Nodal signaling on invasion, as we observed that knock down of Nodal, besides reducing ZEB1 and Snail, significantly inhibited metastatic potential both in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 91%

Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Asnaghi

White

Yoon

et al. 2019

acta neuropathol commun

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Retinoblastoma is the most common intraocular malignancy in children. We previously found that the ACVR1C/SMAD2 pathway is significantly upregulated in invasive retinoblastoma samples from patients. Here we studied the role of an ACVR1C ligand, Nodal, in regulating growth and metastatic dissemination in retinoblastoma. Inhibition of Nodal using multiple short hairpin (shRNAs) in WERI Rb1 and Y79 retinoblastoma cell cultures reduced growth by more than 90%, as determined by CCK-8 growth assay. Proliferation was also significantly inhibited, as found by Ki67 assay. These effects were paralleled by inhibition in the phosphorylation of the downstream effector SMAD2, as well as induction of apoptosis, as we observed more than three-fold increase in the percentage of cells positive for cleaved-caspase-3 or expressing cleaved-PARP1. Importantly, we found that downregulation of Nodal potently suppressed invasion in vitro, by 50 to 80%, as determined by transwell invasion assay ( p = 0.02). Using an orthotopic model of retinoblastoma in zebrafish, we found 34% reduction in the ability of the cells to disseminate outside the eye, when Nodal was knocked down by shRNA ( p = 0.0003). These data suggest that Nodal plays an important role in promoting growth, proliferation and invasion in retinoblastoma, and can be considered a new therapeutic target for both primary tumor growth and metastatic progression.

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Section: Discussionsupporting

confidence: 91%

Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Asnaghi

White

Yoon

et al. 2019

acta neuropathol commun

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“…TGF-β1 can trigger EMT in neuroblastoma. In fact, E-cadherin significantly decreases, whereas α-SMA significantly increases after neuroblastoma cells are treated with different concentrations of TGF-β1 [78] and increase Slug and Zeb-1 expression [79]. Both N-Myc and c-Myc proteins in NB can bind and activate the TWIST1 promoter.…”

Section: Neuroblastomamentioning

confidence: 95%

Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors

Donato

Presta

Arcidiacono

et al. 2020

Cancers

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In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests (NC) contribute to the development of multiple cell types including melanocytes, craniofacial cartilage, glia, neurons, peripheral and enteric nervous systems, and the adrenal medulla. This plastic performance is due to an accurate program of gene expression orchestrated with cellular/extracellular signals finalized to regulate long-distance migration, proliferation, differentiation, apoptosis, and survival. During neurulation, prior to initiating their migration, NC cells must undergo an epithelial–mesenchymal transition (EMT) in which they alter their actin cytoskeleton, lose their cell–cell junctions, apicobasal polarity, and acquire a motile phenotype. Similarly, during the development of the tumors derived from neural crests, comprising a heterogeneous group of neoplasms (Neural crest-derived tumors (NCDTs)), a group of genes responsible for the EMT pathway is activated. Here, retracing the molecular pathways performed by pluripotent cells at the boundary between neural and non-neural ectoderm in relation to the natural history of NCDT, points of contact or interposition are highlighted to better explain the intricate interplay between cancer cells and the innate and adaptive immune response.

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“…Nodal can increase the malignancy of neuroblastoma cells by enhancing ZEB1 activity. Knockdown of ZEB1 attenuates Nodal-induced malignancy, and Nodal increases the protein stability of ZEB1 via phosphorylation mediated by Ataxia telangiectasia mutated kinase (ATM), rather than affecting its mRNA expression [107]. In human SH-SY5Y cells, miR-205 is positively regulated by Angelica polysaccharide and targets ZEB1 [108].…”

Section: Neuroblastomamentioning

confidence: 99%

Oncogenic functions of ZEB1 in pediatric solid cancers: interplays with microRNAs and long noncoding RNAs

et al. 2021

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The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activities in cell function and embryonic development, including driving epithelial-mesenchymal transition. Several aspects of ZEB1 function can be regulated by its functional interactions with noncoding RNA types, namely microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Increasing evidence indicates that ZEB1 importantly influences cancer initiation, tumor progression, metastasis, and resistance to treatment. Cancer is the main disease-related cause of death in children and adolescents. Although the role of ZEB1 in pediatric cancer is still poorly understood, emerging findings have shown that it is expressed and regulates childhood solid tumors including osteosarcoma, retinoblastoma, neuroblastoma, and central nervous system tumors. Here, we review the evidence supporting a role for ZEB1, and its interplays with miRNAs and lncRNAs, in pediatric cancers.

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Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Cited by 3 publications

References 38 publications

Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors

Oncogenic functions of ZEB1 in pediatric solid cancers: interplays with microRNAs and long noncoding RNAs

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